The human immunodeficiency virus (HIV) is a pathogenic retrovirus and the causative agent of acquired immune deficiency syndrome (AIDS) and related disorders (Barre-Sinossi, F. et al.; 1983, Science 220:868-870; Gallo, R. et al., 1984, Science 224:500-503). There are at least two distinct types of HIV-1 (Barre-Sinossi, F. et al.; 1983, Science 220:868-870; Gallo, R. et al., 1984, Science 224:500-503) and HIV-2 (Clavel. F. et al., 1986, Science 223:343-346; Guyader, M. et al., 1987, Nature 326:662-669). Further, a large amount of genetic heterogeneity exists within populations of each of these types. Infection of human CD-4+T-lymphocytes with an HIV virus leads to depletion of the cell type and eventually to opportunistic infections, neurological dysfunctions, neoplastic growth, and untimely death.
HIV is a member of the lentivirus family of retroviruses (Teich, N. et al., 1984; RNA Tumor Viruses, Weiss, R. et al., eds., CSH-press, pp. 949-956). Retroviruses are small enveloped viruses that contain a diploid, single-stranded RNA genome, and replicate via a DNA intermediate produced by a virally-encoded reverse transcriptase, an RNA-dependent DNA polymerase (Varmus, H., 1988, Science 240:1427-1439). Other retroviruses include, for example, oncogenic viruses such as human T-cell leukemia viruses (HTLV-1,-II,-III), and feline leukemia virus. The HIV viral particle consists of a viral core, made up of proteins designated p24 and p18. The viral core contains the viral RNA genome and those enzymes required for replicative events. Myristylated gag protein forms an outer viral shell around the viral core, which is, in turn, surrounded by a lipid membrane envelope derived from the infected cell membrane.
The HIV envelope surface glycoproteins are synthesized as a single 160 kD precursor protein which is cleaved by a cellular protease during viral budding into two glycoproteins, gp41 and gp120. gp41 is a transmembrane protein and gp120 is an extracellular protein which remains noncovalently associated with gp41, possibly in a trimeric or multimeric form (Hammerwskjold, M. and Rekosh, D., 1989, Biochem. Biophys. Acta 989:269-280).
Attention is also being given to the development of vaccines for the treatment of HIV infection. The HIV-1 envelope proteins (gp160, gp120, gp41) have been shown to be the major antigens for anti-HIV antibodies present in AIDS patients (Barin et al., 1985, Science 228:1094-1096). Thus far, these proteins seem to be the most promising candidates to act as antigens for anti-HIV development. To this end, several groups have begun to use various portions of gp160, gp120, and/or gp41 as immunogenic targets for the host immune systems. See for example, Ivanoff, L. et al., U.S. Pat. No. 5,141,867; Saith, G. et al., WO 92/22,654; Schafferman, A., WO 91/09872; Formoso, C. et al., WO 90/07119. Clinical results concerning these candidate vaccines, however, still remain far in the future.
U.S. Pat. No. 5,541,206 and EP 0674513 B1 discloses the synthesis of Ritonavir.
U.S. Pat. No. 5,541,206 discloses the use of ritonavir to inhibit an HIV infection.
U.S. Pat. No. 5,674,882 discloses the use of ritonavir in combination with one or more HIV protease inhibitors to inhibit an HIV infection.
U.S. Pat. No. 6,037,157 and WO 97/01349 discloses the use of ritonavir to enhance the pharmacokinetics of compounds metabolized by cytochrome P450 monooxygenase.
U.S. Pat. No. 5,484,801 discloses a liquid dosage form of ritonavir for oral administration.
WO 95/07696 discloses an encapsulated solid or semi-solid dosage form for ritonavir.
WO 99/67254 discloses the synthesis of darunavir and the manner in which it may be used to treat HIV infection.
WO 99/67254 discloses the dosage forms suitable for the oral administration of darunavir.
U.S. 2007/0208009 discloses a combination comprising tenofovir, ritonavir and darunavir for treatment or prevention of HIV infections.
None of the current AIDS treatments have proven to be totally effective in treating and/or reversing the disease. In addition, many of the compounds currently used to treat AIDS cause adverse side effects including low platelet count, renal toxicity and bone marrow cytopenia.
Some drugs and, in particular, some HIV protease inhibitors are metabolized by cytochrome P450 monooxygenase, leading to unfavorable pharmacokinetics and hence require more frequent and higher doses, although administration of such drugs with an agent that inhibits metabolism by cytochrome P450 monooxygenase will improve the pharmacokinetics (i.e., increase half-life, increase the time to peak plasma concentration, increase blood levels) of the drug.
Moreover, combination therapy is potentially problematic given the high toxicity of most anti-HIV therapeutics and their low level of effectiveness. Thus, there is a need of a combination therapy which is effective yet non-toxic for treatment-naïve and treatment experienced patients.
Surprisingly, the present inventors have found that a selective combination of darunavir and ritonavir with pharmaceutically acceptable excipients and using simpler manufacturing processes achieves the desired formulation.
We have found that both the actives when admixed per se, show incompatibility and hence there is a need to formulate a stable dosage form.